ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2011
Spinal synthesis of estrogen and concomitant signaling by membrane estrogen receptors regulate spinal κ- and μ-opioid receptor heterodimerization and female-specific spinal morphine antinociception.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 85 citations in OpenAlex.
- The Role of Kappa-Opioid Receptor/Dynorphin System in Modulating Neural-Circuits of Depression and Anxiety-A Review.Journal of cellular and molecular medicine · 2026Review
- Sexual Dimorphism in Spinal Cord Injury: From Molecular Mechanisms to Clinical Translation.Neuromolecular medicine · 2026Review
- The role of gonadal hormones in regulating opioid antinociception.Annals of medicine · 2024Review
- Dynorphin/kappa opioid receptor system regulation on amygdaloid circuitry: Implications for neuropsychiatric disorders.Frontiers in systems neuroscience · 2022Review
- Class A and C GPCR Dimers in Neurodegenerative Diseases.Current neuropharmacology · 2022Review
- Arbiters of endogenous opioid analgesia: role of CNS estrogenic and glutamatergic systems.Translational research : the journal of laboratory and clinical medicine · 2021Review
- Estrogen receptors in pain modulation: cellular signaling.Biology of sex differences · 2021Review
- The Antitumor Peptide ERα17p Exerts Anti-Hyperalgesic and Anti-Inflammatory Actions Through GPER in Mice.Frontiers in endocrinology · 2021Article
- Emotionality vs. Other Biobehavioural Traits: A Look at Neurochemical Biomarkers for Their Differentiation.Frontiers in psychology · 2021Review
- Sex differences in the modulation of mouse nest building behavior by kappa opioid receptor signaling.Neuropharmacology · 2020Article
- Sex Differences in Animal Models of Opioid Reward.Current sexual health reports · 2020Article
- Phosphorylation of unique C-terminal sites of the mu-opioid receptor variants 1B2 and 1C1 influences their Gs association following chronic morphine.Journal of neurochemistry · 2020Article
- Mu Opioid Receptor Heterodimers Emerge as Novel Therapeutic Targets: Recent Progress and Future Perspective.Frontiers in pharmacology · 2020Review
- Sex differences in fear extinction.Neuroscience and biobehavioral reviews · 2019Review
- Activation of Membrane Estrogen Receptors Attenuates NOP-Mediated Tactile Antihypersensitivity in a Rodent Model of Neuropathic Pain.Brain sciences · 2019Article
- Pharmacological Modulation of Endogenous Opioid Activity to Attenuate Neuropathic Pain in Rats.The journal of pain · 2019Article
- Review
- Estrogens as arbiters of sex-specific and reproductive cycle-dependent opioid analgesic mechanisms.Vitamins and hormones · 2019Article
- Estrogen Regulation of GRK2 Inactivates Kappa Opioid Receptor Signaling Mediating Analgesia, But Not Aversion.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Article
Corrections and comments
- Erratum issued
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
We previously demonstrated that the spinal cord κ-opioid receptor (KOR) and μ-opioid receptor (MOR) form heterodimers (KOR/MOR). KOR/MOR formation and the associated KOR dependency of spinal morphine antinociception are most robust during proestrus. Using Sprague Dawley rats, we now demonstrate that (1) spinal synthesis of estrogen is critical to these processes, and (2) blockade of either estrogen receptor (ER) α-, β-, or G-protein-coupled ER1 or progesterone receptor (PR) substantially reduces KOR/MOR and eliminates mediation by KOR of spinal morphine antinociception. Effects of blocking ERs were manifest within 15 min, whereas those of PR blockade were manifest after 18 h, indicating the requirement for rapid signaling by estrogen and transcriptional effects of progesterone. Individual or combined blockade of ERs produced the same magnitude of effect, suggesting that they work in tandem as part of a macromolecular complex to regulate KOR/MOR formation. Consistent with this inference, we found that KOR and MOR were coexpressed with ERα and G-protein-coupled ER1 in the spinal dorsal horn. Reduction of KOR/MOR by ER or PR blockade or spinal aromatase inhibition shifts spinal morphine antinociception from KOR dependent to KOR independent. This indicates a sex steroid-dependent plasticity of spinal KOR functionality, which could explain the greater analgesic potency of KOR agonists in women versus men. We suggest that KOR/MOR is a molecular switch that shifts the function of KOR and thereby endogenous dynorphin from pronociceptive to antinociceptive. KOR/MOR could thus serve as a novel molecular target for pain management in women.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.